Direct, enantioselective aldol coupling of aldehydes using chiral organic catalysts

ABSTRACT

Nonmetallic, chiral organic catalysts are used to catalyze an enantioselective aldol coupling reaction between aldehyde substrates. The reaction may be carried out with a single enolizable aldehyde, resulting in dimerization to give a β-hydroxy aldehyde, or trimerization to give a dihydroxy tetrahydropyran. The reaction may also conducted with an enolizable aldehyde and a second aldehyde, which may or may not be enolizable, so that the coupling is a cross-aldol reaction in which the α-carbon of the enolizable aldehyde adds to the carbonyl carbon of the second aldehyde in an enantioselective fashion. Reaction systems composed of at least one enolizable aldehyde, an optional additional aldehyde, and the nonmetallic chiral organic catalyst are also provided, as are methods of implementing the enantioselective aldol reaction in the synthesis of sugars.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e)(1) toprovisional U.S. Patent Applications Serial No. 60/373,871, filed Apr.19, 2002, and No. 60/376,878, filed May 1, 2002. The disclosures of theaforementioned applications are incorporated by reference in theirentireties.

TECHNICAL FIELD

[0002] This invention relates generally to catalysis of enantioselectivereactions, and more particularly relates to enantioselective reactionsinvolving the use of chiral organic compounds to catalyze the directcoupling of aldehydes via an aldol reaction. The invention has utilityin the fields of catalysis and organic synthesis, includingorganocatalysis and chiral chemistry.

BACKGROUND

[0003] The aldol reaction is one of the fundamental synthetic routesused by organic chemists to form new carbon-carbon bonds. The reactioninvolves the addition of a first aldehyde or ketone, as a nucleophile,to a second aldehyde or ketone that acts as an electrophile.Mechanistically, the α-carbon atom of the first aldehyde or ketone addsto the carbonyl carbon of the second aldehyde or ketone. The product isa β-hydroxy aldehyde (i.e., an “aldol”) or ketone, which may serve as anintermediate in the context of a more complex reaction, or may representthe final product. Conventionally, aldol reactions involve a preliminarystep in which the first aldehyde or ketone is converted to a nucleophileby forming the corresponding enolate, using a base, or the correspondingenol, using an acid.

[0004] Over the last three decades, seminal research has established thealdol reaction as the principal chemical reaction for thestereoselective construction of complex polyol architecture. Evans etal. (1979) J. Am. Chem. Soc. 101:6120; Evans et al. (1981) J. Am. Chem.Soc. 103:2127; Heathcock, C. H. Asymmetric Synthesis; Morrion, J. D.,Ed.; Academic Press: New York, 1984; Vol. 3, part B, p 111; Danda et al.(1980) J. Org. Chem. 55:173; Masamune et al. (1981) J. Am. Chem. Soc.103:1566; Masamune et al. (1986) J. Am. Chem. Soc. 108:8279; Mukaiyama,“The Directed Aldol Reaction,” in Organic Reactions, New York, 1982;Vol. 28, p 203; Kobayashi et al. (1993) Tetrahedron 49:1761. Morerecently, several researchers have described attempts to achieveenantioselective “direct” aldol reactions, i.e., aldol reactions that donot require the pregeneration of enolates or enolate equivalents. See,e.g., List et al. (2000) J. Am. Chem. Soc. 122:2395; Notz et al. (2000)J. Am. Chem. Soc. 122:7386; Trost et al. (2000) J. Am. Chem. Soc.122:12003; Yamada et al. (1997) Angew. Chem. Int. Ed. Engl. 36:1871;Yoshikawa et al. (1999) J. Am. Chem. Soc. 121:4168. These efforts havegiven rise to a new goal, the development of catalytic methods thatallow the direct coupling of aldehyde substrates, illustrated in Scheme1:

[0005] To date, direct, enantioselective coupling of aldehyde substrateshas been achieved only with enzymatic catalysis (see Gijsen et al.(1994) J. Am. Chem. Soc. 116:8422). In addition, the enantioselectivealdol coupling of non-equivalent aldehydes has been viewed as aparticularly formidable synthetic challenge, because of (i) thepropensity of aldehydes to polymerize under metal-catalyzed conditionsand (ii) the mechanistic requirement that non-equivalent aldehydes mustselectively partition into two discrete components, a nucleophilic donorand an electrophilic acceptor. Accordingly, an efficient andoperationally simple method for carrying out direct, enantioselectivecoupling of aldehydes, including non-equivalent aldehydes, would be anenormously powerful tool in the field of synthetic organic chemistry.The present invention now provides such a method using chiral organiccatalysts.

[0006] Many catalysts of organic reactions, including aldol couplingreactions, are organometallic complexes. Unfortunately, manyorganometallic reagents are expensive, and, depending on their catalyticactivity, they may not be commercially viable. Moreover, manyorganometallic complexes are useful in conjunction with very specificreactants and reactions, a problem that is exacerbated in the catalysisof reactions leading to chiral molecules, particularly the conversion ofeither chiral or achiral molecules via enantioselective catalysis toprovide a chiral product. Despite the observed need, relatively fewasymmetric transformations have been reported that employ organicmolecules as reaction catalysts. Recently, as described in U.S. Pat. No.6,307,057 to MacMillan and U.S. Pat. No. 6,369,243 to MacMillan et al.,certain organic catalysts have been synthesized that facilitateenantioselective transformations by lowering the LUMO (lowest unoccupiedmolecular orbital) of a reactant such as an α,β-unsaturated carbonylcompound to facilitate reaction thereof. The organic catalysts are acidaddition salts of nonmetallic compounds containing a Group 15 or Group16 heteroatom, e.g., salts of chiral amines, exemplified by theimidazolidinone salt (5S)-5-benzyl-2,2,3-trimethyl-imidazolidin-4-onehydrochloride

[0007] It has now been quite unexpectedly discovered that certainimidazolidinones and other chiral organic compounds, including, withoutlimitation, those described in the '057 and '243 patents, are useful incatalyzing aldol coupling reactions of aldehydes in an enantioselectivefashion. The invention represents a significant advance in the field ofsynthetic organic chemistry, insofar as the present methodology enablesnot only enantioselective aldol reactions of aldehydes, but also direct,enantioselective aldol coupling reactions using aldehydes as both aldoldonor and aldol acceptor. The method provides for the enantioselectiveaccess to β-hydroxy aldehydes—important synthons in polypropionate andpolyacetate natural product synthesis—as well as hydroxyvinyl polymersand oxygen heterocycles, including naturally occurring and syntheticsugars.

SUMMARY OF THE INVENTION

[0008] Accordingly, the invention provides a method for carrying out analdol reaction using aldehydes as both aldol donor and the aldolacceptor, i.e., as the nucleophilic and electrophilic reactants,respectively. The reaction is carried out catalytically, using anonmetallic, organic compound as the catalyst. The catalysts are readilysynthesized from inexpensive, commercially available reagents,compatible with aerobic conditions, and provide the desired aldolcoupling products in excellent yields with a high level ofenantioselectivity.

[0009] In a first aspect of the invention, then, a method is providedfor carrying out an enantioselective aldol coupling reaction betweenaldehyde molecules, comprising contacting (a) an enolizable aldehyde andoptionally (b) an additional aldehyde, with (c) a catalyticallyeffective amount of a nonmetallic chiral catalyst containing a Group 15or Group 16 heteroatom. Any enolizable aldehyde may be employed, meaningthat the aldehyde may be substituted with any nonhydrogen substituent(provided that the substituent not interfere with the aldol couplingreaction), so long as the α-carbon of the aldehyde contains a singleenolizable hydrogen atom. With a single enolizable aldehyde, thereaction will proceed as a dimerization or trimerization reaction,resulting in a β-hydroxy aldehyde or a dihydroxy tetrahydropyran. Suchreactions are illustrated below:

[0010] R¹ is selected from hydrocarbyl, substituted hydrocarbyl,heteroatom-containing hydrocarbyl, substituted heteroatom-containinghydrocarbyl, and functional groups. Preferred catalysts are cyclicsecondary amines, exemplified by L-proline,(2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one, and salts andanalogs thereof. When two or more aldehyde reactants are employed, thereaction proceeds as a “cross-aldol” reaction in which the α-carbon ofan enolizable aldehyde undergoes nucleophilic addition to the carbonylcarbon of an additional aldehyde. The second aldehyde may or may not beenolizable, and is generally represented by formula (II)

[0011] in which R² is defined as for R¹.

[0012] The reaction product(s) of the present aldol coupling reactionsmay be isolated, purified, and subject to further reaction, wherein, forexample, a hydroxyl group is protected, derivatized as an ether, ester,or the like, or used as a nucleophile in a reaction with anelectrophilic co-reactant, or a carbonyl group is reduced to a hydroxylgroup or modified via a further nucleophilic addition reaction, e.g., ina further aldol reaction with an additional carbonyl-containingcompound. Alternatively, further reaction may be carried out in thecontext of a “one-pot” synthesis, in which case the initial product ofthe aldol reaction is not isolated prior to subsequent modification.

[0013] The method of the invention may be implemented in theenantioselective, organocatalyzed synthesis of sugar molecules, when anenolizable aldehyde bearing a protected α-hydroxy group is used as asubstrate. Such a substrate is generally of formula (I) wherein R¹ is—O—Pr in which Pr is a hydroxyl-protecting group. In most cases, it isdesirable that the aldol coupling reaction proceed so as to result intrimerization of at least one enolizable aldehyde to give a protecteddihydroxy tetrahydropyran. Alternatively, the aldol coupling reactioncan result in dimerization of at least one enolizable aldehyde, and thedimer so provided is then further reacted, e.g., in an additional aldolreaction, to give a protected dihydroxy tetrahydropyran. In a preferredsugar synthesis, two enolizable aldehydes each α-substituted with aprotected hydroxyl group are used as substrates, wherein the protectedhydroxyl group of the first enolizable aldehyde is of the formula —O—Pr¹and the protected hydroxyl group of the second enolizable aldehyde is ofthe formula —O—Pr², and Pr¹ and Pr² are different, preferablyorthogonally removable under conditions generally used in carbohydratesynthesis.

[0014] In another embodiment, a reaction system is provided thatcomprises a nonmetallic chiral catalyst containing a Group 15 or Group16 heteroatom, an enolizable aldehyde having the structure of formula(I) and, optionally, an additional aldehyde has the structure of formula(II)

[0015] in which R¹ and R² are defined above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Unless otherwise indicated, the invention is not limited tospecific molecular structures, substituents, synthetic methods, reactionconditions, or the like, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only and is not intended to be limiting.

[0017] As used in the specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “acatalyst” includes a single catalyst as well as a combination or mixtureof two or more catalysts, reference to “a substituent” encompasses asingle substituent as well as two or more substituents, and the like.

[0018] In this specification and in the claims that follow, referencewill be made to a number of terms, which shall be defined to have thefollowing meanings:

[0019] The term “alkyl” as used herein refers to a linear, branched, orcyclic saturated hydrocarbon group typically although not necessarilycontaining 1 to about 24 carbon atoms, preferably 1 to about 12 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups suchas cyclopentyl, cyclohexyl and the like. Generally, although again notnecessarily, alkyl groups herein contain 1 to about 12 carbon atoms. Theterm “lower alkyl” intends an alkyl group of 1 to 6 carbon atoms, andthe specific term “cycloalkyl” intends a cyclic alkyl group, typicallyhaving 4 to 8, preferably 5 to 7, carbon atoms. The term “substitutedalkyl” refers to alkyl substituted with one or more substituent groups,and the terms “heteroatom-containing alkyl” and “heteroalkyl” refer toalkyl in which at least one carbon atom is replaced with a heteroatom.If not otherwise indicated, the terms “alkyl” and “lower alkyl” includelinear, branched, cyclic, unsubstituted, substituted, and/orheteroatom-containing alkyl and lower alkyl, respectively.

[0020] The term “alkylene” as used herein refers to a difunctionallinear, branched, or cyclic alkyl group, where “alkyl” is as definedabove.

[0021] The term “alkenyl” as used herein refers to a linear, branched,or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing atleast one double bond, such as ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl,eicosenyl, tetracosenyl, and the like. Preferred alkenyl groups hereincontain 2 to about 12 carbon atoms. The term “lower alkenyl” intends analkenyl group of 2 to 6 carbon atoms, and the specific term“cycloalkenyl” intends a cyclic alkenyl group, preferably having 5 to 8carbon atoms. The term “substituted alkenyl” refers to alkenylsubstituted with one or more substituent groups, and the terms“heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl inwhich at least one carbon atom is replaced with a heteroatom. If nototherwise indicated, the terms “alkenyl” and “lower alkenyl” includelinear, branched, cyclic, unsubstituted, substituted, and/orheteroatom-containing alkenyl and lower alkenyl, respectively.

[0022] The term “alkenylene” as used herein refers to a difunctionallinear, branched, or cyclic alkenyl group, where “alkenyl” is as definedabove.

[0023] The term “alkynyl” as used herein refers to a linear or branchedhydrocarbon group of 2 to about 24 carbon atoms containing at least onetriple bond, such as ethynyl, n-propynyl, and the like. Preferredalkynyl groups herein contain 2 to about 12 carbon atoms. The term“lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms. Theterm “substituted alkynyl” refers to alkynyl substituted with one ormore substituent groups, and the terms “heteroatom-containing alkynyl”and “heteroalkynyl” refer to alkynyl in which at least one carbon atomis replaced with a heteroatom. If not otherwise indicated, the terms“alkynyl” and “lower alkynyl” include linear, branched, unsubstituted,substituted, and/or heteroatom-containing alkynyl and lower alkynyl,respectively.

[0024] The term “alkoxy” as used herein intends an alkyl group boundthrough a single, terminal ether linkage; that is, an “alkoxy” group maybe represented as —O-alkyl where alkyl is as defined above. A “loweralkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms.Analogously, “alkenyloxy” and “lower alkenyloxy” respectively refer toan alkenyl and lower alkenyl group bound through a single, terminalether linkage, and “alkynyloxy” and “lower alkynyloxy” respectivelyrefer to an alkynyl and lower alkynyl group bound through a single,terminal ether linkage.

[0025] The term “aryl” as used herein, and unless otherwise specified,refers to an aromatic substituent containing a single aromatic ring ormultiple aromatic rings that are fused together, directly linked, orindirectly linked (such that the different aromatic rings are bound to acommon group such as a methylene or ethylene moiety). Preferred arylgroups contain 5 to 24 carbon atoms, and particularly preferred arylgroups contain 5 to 14 carbon atoms. Exemplary aryl groups contain onearomatic ring or two fused or linked aromatic rings, e.g., phenyl,naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and thelike. “Substituted aryl” refers to an aryl moiety substituted with oneor more substituent groups, and the terms “heteroatom-containing aryl”and “heteroaryl” refer to aryl substituents in which at least one carbonatom is replaced with a heteroatom, as will be described in furtherdetail infra.

[0026] The term “aryloxy” as used herein refers to an aryl group boundthrough a single, terminal ether linkage, wherein “aryl” is as definedabove. An “aryloxy” group may be represented as —O-aryl where aryl is asdefined above. Preferred aryloxy groups contain 5 to 24 carbon atoms,and particularly preferred aryloxy groups contain 5 to 14 carbon atoms.Examples of aryloxy groups include, without limitation, phenoxy,o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy,m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy,3,4,5-trimethoxy-phenoxy, and the like.

[0027] The term “alkaryl” refers to an aryl group with an alkylsubstituent, and the term “aralkyl” refers to an alkyl group with anaryl substituent, wherein “aryl” and “alkyl” are as defined above.Preferred alkaryl and aralkyl groups contain 6 to 24 carbon atoms, andparticularly preferred alkaryl and aralkyl groups contain 6 to 16 carbonatoms. Alkaryl groups include, for example, p-methylphenyl,2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl,7-cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like.Examples of aralkyl groups include, without limitation, benzyl,2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl,4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl,4-benzylcyclohexylmethyl, and the like. The terms “alkaryloxy” and“aralkyloxy” refer to substituents of the formula —OR wherein R isalkaryl or aralkyl, respectively, as just defined.

[0028] The terms “cyclic” and “ring” refer to alicyclic or aromaticgroups that may or may not be substituted and/or heteroatom containing,and that may be monocyclic, bicyclic, or polycyclic. The term“alicyclic” is used in the conventional sense to refer to an aliphaticcyclic moiety, as opposed to an aromatic cyclic moiety, and may bemonocyclic, bicyclic or polycyclic.

[0029] The terms “halo” and “halogen” are used in the conventional senseto refer to a chloro, bromo, fluoro or iodo substituent.

[0030] “Hydrocarbyl” refers to univalent hydrocarbyl radicals containing1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, mostpreferably 1 to about 12 carbon atoms, including linear, branched,cyclic, saturated and unsaturated species, such as alkyl groups, alkenylgroups, aryl groups, and the like. The term “lower hydrocarbyl” intendsa hydrocarbyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbonatoms, and the term “hydrocarbylene” intends a divalent hydrocarbylmoiety containing 1 to about 30 carbon atoms, preferably 1 to about 24carbon atoms, most preferably 1 to about 12 carbon atoms, includinglinear, branched, cyclic, saturated and unsaturated species. The term“lower hydrocarbylene” intends a hydrocarbylene group of 1 to 6 carbonatoms. “Substituted hydrocarbyl” refers to hydrocarbyl substituted withone or more substituent groups, and the terms “heteroatom-containinghydrocarbyl” and “heterohydrocarbyl” refer to hydrocarbyl in which atleast one carbon atom is replaced with a heteroatom. Similarly,“substituted hydrocarbylene” refers to hydrocarbylene substituted withone or more substituent groups, and the terms “heteroatom-containinghydrocarbylene” and “heterohydrocarbylene” refer to hydrocarbylene inwhich at least one carbon atom is replaced with a heteroatom. Unlessotherwise indicated, the term “hydrocarbyl” and “hydrocarbylene” are tobe interpreted as including substituted and/or heteroatom-containinghydrocarbyl and hydrocarbylene moieties, respectively.

[0031] The term “heteroatom-containing” as in a “heteroatom-containinghydrocarbyl group” refers to a hydrocarbon molecule or a hydrocarbylmolecular fragment in which one or more carbon atoms is replaced with anatom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus orsilicon, typically nitrogen, oxygen or sulfur. Similarly, the term“heteroalkyl” refers to an alkyl substituent that isheteroatom-containing, the term “heterocyclic” refers to a cyclicsubstituent that is heteroatom-containing, the terms “heteroaryl” and“heteroaromatic” respectively refer to “aryl” and “aromatic”substituents that are heteroatom-containing, and the like. It should benoted that a “heterocyclic” group or compound may or may not bearomatic, and further that “heterocycles” may be monocyclic, bicyclic,or polycyclic as described above with respect to the term “aryl.”Examples of heteroalkyl groups include alkoxyaryl,alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl,pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl,1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containingalicyclic groups are pyrrolidino, morpholino, piperazino, piperidino,etc.

[0032] By “substituted” as in “substituted hydrocarbyl,” “substitutedalkyl,” “substituted aryl,” and the like, as alluded to in some of theaforementioned definitions, is meant that in the hydrocarbyl, alkyl,aryl, or other moiety, at least one hydrogen atom bound to a carbon (orother) atom is replaced with one or more non-hydrogen substituents.Examples of such substituents include, without limitation: functionalgroups referred to herein as “Fn,” such as halo, hydroxyl, sulfhydryl,C₁-C₂₄ alkoxy, C₂-C₂₄ alkenyloxy, C₂-C₂₄ alkynyloxy, C₅-C₂₄ aryloxy,C₆-C₂₄ aralkyloxy, C₆-C₂₄ alkaryloxy, acyl (including C₂-C₂₄alkylcarbonyl (—CO-alkyl) and C₆-C₂₄ arylcarbonyl (—CO-aryl)), acyloxy(—O-acyl, including C₂-C₂₄ alkylcarbonyloxy (—O—CO-alkyl) and C₆-C₂₄arylcarbonyloxy (—O—CO-aryl)), C₂-C₂₄ alkoxycarbonyl (—(CO)—O-alkyl),C₆-C₂₄ aryloxycarbonyl (—(CO)—O-aryl), halocarbonyl (—CO)—X where X ishalo), C₂-C₂₄ alkylcarbonato (—O—(CO)—O-alkyl), C₆-C₂₄ arylcarbonato(—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO⁻), carbamoyl(—(CO)—NH₂), mono-(C₁-C₂₄ alkyl)-substituted carbamoyl (—(CO)—NH(C₁-C₂₄alkyl)), di-(C₁-C₂₄ alkyl)-substituted carbamoyl (—(CO)—N(C₁-C₂₄alkyl)₂), mono-(C₅-C₂₄ aryl)-substituted carbamoyl (—(CO)—NH-aryl),di-(C₅-C₂₄ aryl)-substituted carbamoyl (—(CO)—N(C₅-C₂₄ aryl)₂),di-N-(C₁-C₂₄ alkyl),N-(C₅-C₂₄ aryl)-substituted carbamoyl, thiocarbamoyl(—(CS)—NH₂), mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl(—(CO)—NH(C₁-C₂₄ alkyl)), di-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl(—(CO)—N(C₁-C₂₄ alkyl)₂), mono-(C₅-C₂₄ aryl)-substituted thiocarbamoyl(—(CO)—NH-aryl), di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl(—(CO)—N(C₅-C₂₄ aryl)₂), di-N-(C₁-C₂₄ alkyl),N-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, carbamido (—NH—(CO)—NH₂), cyano(—C≡N), cyanato (—O—C≡N),thiocyanato (—S—CN), formyl (—(CO)—H), thioformyl (—(CS)—H), amino(—NH₂), mono-(C₁-C₂₄ alkyl)-substituted amino, di-(C₁-C₂₄alkyl)-substituted amino, mono-(C₅-C₂₄ aryl)-substituted amino,di-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄ alkylamido (—NH—(CO)-alkyl),C₆-C₂₄ arylamido (—NH—(CO)-aryl), imino (—CR═NH where R=hydrogen, C₁-C₂₄alkyl, C₅-C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), C₂-C₂₀alkylimino (—CR═N(alkyl), where R=hydrogen, C₁-C₂₄ alkyl, C₅-C₂₄ aryl,C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl, etc.), arylimino (—CR═N(aryl), whereR=hydrogen, C₁-C₂₀ alkyl, C₅-C₂₄ aryl, C₆-C₂₄ alkaryl, C₆-C₂₄ aralkyl,etc.), nitro (—NO₂), nitroso (—NO), sulfo (—SO₂—OH), sulfonato(—SO₂—O⁻), C₁-C₂₄ alkylsulfanyl (—S-alkyl; also termed “alkylthio”),C₅-C₂₄ arylsulfanyl (—S-aryl; also termed “arylthio”), C₁-C₂₄alkylsulfinyl (—(SO)-alkyl), C₅-C₂₄arylsulfinyl (—(SO)-aryl), C₁-C₂₄alkylsulfonyl (—SO₂-alkyl), C₅-C₂₄ arylsulfonyl (—SO₂-aryl), boryl(—BH₂), borono (—B(OH)₂), boronato (—B(OR)₂ where R is alkyl or otherhydrocarbyl), phosphono (—P(O)(OH)₂), phosphonato (—P(O)(O⁻)₂),phosphinato (—P(O)(O⁻)), phospho (—PO₂), and phosphino (—PH₂); and thehydrocarbyl moieties C₁-C₂₄ alkyl (preferably C₁-C₁₂ alkyl, morepreferably C₁-C₆ alkyl), C₂-C₂₄ alkenyl (preferably C₂-C₁₂ alkenyl, morepreferably C₂-C₆ alkenyl), C₂-C₂₄ alkynyl (preferably C₂-C₁₂ alkynyl,more preferably C₂-C₆ alkynyl), C₅-C₂₄ aryl (preferably C₅-C₁₄ aryl),C₆-C₂₄ alkaryl (preferably C₆-C₁₆ alkaryl), and C₆-C₂₄ aralkyl(preferably C₆-C₁₆ aralkyl).

[0033] In addition, the aforementioned functional groups may, if aparticular group permits, be further substituted with one or moreadditional functional groups or with one or more hydrocarbyl moietiessuch as those specifically enumerated above. Analogously, theabove-mentioned hydrocarbyl moieties may be further substituted with oneor more functional groups or additional hydrocarbyl moieties such asthose specifically enumerated.

[0034] “Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.For example, the phrase “optionally substituted” means that anon-hydrogen substituent may or may not be present on a given atom, and,thus, the description includes structures wherein a non-hydrogensubstituent is present and structures wherein a non-hydrogen substituentis not present.

[0035] The term “chiral” refers to a structure that does not have animproper rotation axis (S_(n)), i.e., it belongs to point group C_(n) orD_(n). Such molecules are thus chiral with respect to an axis, plane orcenter of asymmetry. Preferred “chiral” molecules herein are inenantiomerically pure form, such that a particular chiral moleculerepresents at least about 95 wt. % of the composition in which it iscontained, more preferably at least about 99 wt. % of that composition.

[0036] The term “enantioselective” refers to a chemical reaction thatpreferentially results in one enantiomer relative to a secondenantiomer, i.e., gives rise to a product of which a desired enantiomerrepresents at least about 50 wt. %. Preferably, in the enantioselectivereactions herein, the desired enantiomer represents at least about 80wt. % of the product, more preferably at least about 85 wt. % of theproduct, optimally at least about 95 wt. % of the product.

[0037] When a functional group, e.g., a hydroxyl, sulfhydryl, or aminogroup, is termed “protected”, this means that the group is in modifiedform to preclude undesired side reactions at the protected site.Suitable protecting groups for the compounds of the present inventionwill be recognized from the present application taking into account thelevel of skill in the art, and with reference to standard textbooks,such as Greene et al., Protective Groups in Organic Synthesis (New York:Wiley, 1991).

[0038] In the molecular structures herein, the use of bold and dashedlines to denote particular conformation of groups follows the IUPACconvention. A bond indicated by a broken line indicates that the groupin question is below the general plane of the molecule as drawn (the “α”configuration), and a bond indicated by a bold line indicates that thegroup at the position in question is above the general plane of themolecule as drawn (the “β” configuration).

[0039] Accordingly, the invention provides a method for using organiccatalysts to carry out an enantioselective aldol reaction usingaldehydes as substrates, i.e., as both aldol donor and aldol acceptor,to provide a chiral β-hydroxy aldehyde in substantially enantiomericallypure form as an intermediate or final product. The catalyst is anonmetallic chiral catalyst containing a Group 15 or Group 16heteroatom, e.g., nitrogen, oxygen, sulfur or phosphorus, and apreferred heteroatom is nitrogen. Oxygen-containing andsulfur-containing catalysts may be, for example, alcohols and thiols,respectively, while phosphorus-containing catalysts will generally bephosphines. Heteroatom-containing activators in which the heteroatom isa nitrogen atom may be primary amines, secondary amines ornitrogen-containing polymers. Preferred amines are secondary amineshaving the structure of formula (III)

[0040] In formula (III), R³ and R⁴ are selected from the groupconsisting of hydrogen, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl,aryl, alkaryl, alkaryl, etc.), substituted hydrocarbyl (e.g.,substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.),heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl,alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), and substitutedheteroatom-containing hydrocarbyl (e.g., substitutedheteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl,etc.), or R³ and R⁴ are taken together to form a substituted orunsubstituted ring structure optionally containing a further heteroatomin addition to the nitrogen atom shown in formula (III). When R³ and R⁴are linked, the ring formed may be, for example, a five- or six-memberedalicyclic or aromatic group, e.g., R³ and R⁴ may together formsubstituted or unsubstituted cyclopentyl, cyclohexyl, pyrrolidinyl,piperidinyl, morpholinyl, pyrrolyl, pyridinyl, pyrimidinyl, imidazolyl,or the like. Preferred compounds are those wherein R³ and R⁴ areindependently selected from the group consisting of methyl, ethyl,propyl, butyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, naphthyl,benzyl and trimethylsilyl, or are linked to form a 3- to 15-membered,optionally substituted cyclic moiety having the structure of formula(IV)

[0041] wherein n is 0 or 1, X is a moiety that contains up to 50 atomsand is selected from the group consisting of hydrocarbylene, substitutedhydrocarbylene, heteroatom-containing hydrocarbylene and substitutedheteroatom-containing hydrocarbylene, and X¹ and X² are independentlysubstituted or unsubstituted methylene. Exemplary such secondary amineshave the structure of formula (V)

[0042] in which R⁵, R⁶, R⁷, and R⁸ are independently selected fromhydrogen, hydroxyl, sulfhydryl, carboxyl, amino, mono-(C₁-C₂₄alkyl)-substituted amino, di-(C₁-C₂₄ alkyl)-substituted amino,mono-(C₅-C₂₄ aryl)-substituted amino, di-(C₅-C₂₄ aryl)-substitutedamino, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino, C₆-C₂₄arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyl, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or R⁵ R⁶, and/or R⁷ and R⁸, may together form an oxomoiety ═O.

[0043] X may be, for example, —(CR⁹R¹⁰)—(X³)_(q)—(CR¹¹R¹²)_(t)—, inwhich case the amine has the structure of formula (VI)

[0044] wherein X³ is O, S, NH, NR¹³, or CR¹⁴R¹⁵, q is zero or 1, t iszero or 1, and R⁹, R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁵ are independentlyselected from hydrogen, hydroxyl, sulfhydryl, carboxyl, amino,mono-(C₁-C₂₄ alkyl)-substituted amino, di-(C₁-C₂₄ alkyl)-substitutedamino, mono-(C₅-C₂₄ aryl)-substituted amino, di-(C₅-C₂₄aryl)-substituted amino, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substitutedamino, C₂-C₂₄ alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino,C₆-C₂₄ arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or R⁹ and R¹⁰, and/or R¹¹ and R¹², together form an oxomoiety ═O; and R¹³ is selected from C₁-C₁₂ hydrocarbyl, substitutedC₁-C₁₂ hydrocarbyl, heteroatom-containing C₁-C₁₂ hydrocarbyl, andsubstituted heteroatom-containing C₁-C₁₂ hydrocarbyl.

[0045] In one preferred group of catalysts, q is zero, t is 1, and atleast one of R⁵ through R⁸ is an acidic substituent such as a carboxylgroup, such that the compound is proline or substituted proline. Anexemplary catalyst is L-proline per se, which, as will be appreciated bythose of ordinary skill in the art, corresponds to the structure offormula (VI) when R⁵ through R⁷ and R⁹ through R¹² are hydrogen, and R⁸is β-carboxyl.

[0046] In another group of preferred catalysts, q is 1, X³ is NR¹³, t iszero, R⁵ and R⁷ are hydrogen, and R⁶ is —CR¹⁶R¹⁷R¹⁸, such that thesecondary amine has the structure of formula (VIIA) or (VIIB)

[0047] wherein the various substituents are as follows:

[0048] R⁸ is as defined previously, and preferably has the structure—(L)_(m)—CR¹⁹R²⁰R²¹ wherein m is zero or 1, L is C₁-C₆ alkylene, andR¹⁹, R²⁰ and R²¹ are C₁-C₁₂ hydrocarbyl. More preferred R⁸ substituentsare those wherein m is zero and R¹⁹, R²⁰ and R²¹ are C₁-C₁₂ alkyl.Optimally, R¹⁹, R²⁰ and R²¹ are C₁-C₆ alkyl, e.g., methyl (such that R⁸is then a tert-butyl group).

[0049] R¹³ is selected from C₁-C₁₂ hydrocarbyl (e.g., alkyl, alkenyl,alkynyl, aryl, alkaryl, aralkyl, etc.), substituted C₁-C₁₂ hydrocarbyl(e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl,etc.), heteroatom-containing C₁-C₁₂ hydrocarbyl (e.g.,heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl,etc.), and substituted heteroatom-containing C₁-C₁₂ hydrocarbyl (e.g.,substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl,alkaryl, aralkyl, etc.). Preferred R¹³ substituents are C₁-C₁₂hydrocarbyl such as C₁-C₁₂ alkyl, with C₁-C₆ alkyl groups (e.g., methyl)particularly preferred.

[0050] R¹⁶ and R¹⁷ are independently selected from hydrogen, halo,hydroxyl, C₁-C₁₂ hydrocarbyl, substituted C₁-C₁₂ hydrocarbyl,heteroatom-containing C₁-C₁₂ hydrocarbyl, and substitutedheteroatom-containing C₁-C₁₂ hydrocarbyl. Preferably, R¹⁶ and R¹⁷ arehydrogen or C₁-C₁₂ hydrocarbyl, and, optimally, R¹⁶ and R¹⁷ are bothhydrogen.

[0051] R¹⁸ is a cyclic group optionally substituted with 1 to 4non-hydrogen substituents and containing zero to 3 heteroatoms generallyselected from N, O, and S. In a preferred embodiment, R¹⁸ is monocyclicaryl or heteroaryl optionally substituted with 1 to 4 substituentsselected from halo, hydroxyl, and C₁-C₁₂ hydrocarbyl. More preferably,R¹⁸ is phenyl optionally substituted with 1 or 2 substituents selectedfrom halo, hydroxyl, and C₁-C₆ alkyl, and in a particularly preferredembodiment, R¹⁸ is an unsubstituted phenyl group.

[0052] The catalysts are chiral with respect to an axis, plane or centerof asymmetry, but are generally chiral with a center of asymmetrypresent. It will be appreciated by those skilled in the art that thevarious R groups discussed with respect to the foregoing amines can beselected to create the desired chirality.

[0053] Any of the aforementioned catalysts may also be employed in thepresent reactions in the form of an acid addition salt. That is, thecatalyst may be incorporated into the reaction mixture as an acidaddition salt, or an acid may be added to the reaction mixture to serveas a co-catalyst. The acid used to form the salt or employed as aco-catalyst for the electronically neutral compound is generally,although not necessarily, a Brønsted acid, preferably having a pKa ofless than about 5. Combinations of Brønsted acids may also be used.Suitable acids include both organic and inorganic acids, with inorganicacids including, but not limited to, hydrochloric acid, hydrobromicacid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid,perchloric acid, phosphoric acid, and chromic acid, and with organicacids exemplified by carboxylic acids, sulfonic acids, phosphonic acids,and aromatic alcohols, e.g., phenols, substituted with 1 to 5electron-withdrawing substituents such as nitro, cyano, sulfonato, halo(i.e., Cl, F, Br or I) and halogenated alkyl (typically fluorinatedalkyl, preferably perfluorinated lower alkyl such as trifluoromethyl).Particularly suitable organic acids are carboxylic acids and sulfonicacids having the structural formulas R^(x)—COOH and R^(x)—SO₂—OH whereinR^(x) is aryl, alkyl, substituted aryl (e.g., halogenated aryl), orsubstituted alkyl (e.g., halogenated alkyl, particularly fluorinated andchlorinated alkyl). Preferred R^(x) groups are methyl, halogenatedmethyl (e.g., fluorinated methyl such as trifluoromethyl, chlorinatedmethyl such as chloromethyl, dichloromethyl, and trichloromethyl, etc.),and nitrite-substituted methyl. Specific examples of preferred organicacids include acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, 2-nitrobenzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, triflic acid, p-toluene sulfonic acid, salicylic acid,chloroacetic acid, dichloroacetic acid, trichloroacetic acid,trifluoroacetic acid, and combinations thereof. The Brønsted acid may ormay not be chiral, and those Brønsted acids that are chiral may be usedin isomerically pure form or as a racemic mixture.

[0054] Acid addition salts may be synthesized by admixing theelectronically neutral form of the catalyst (e.g., an imidazolidinone offormula VIIA or VIIB) with a Brønsted acid HX^(A), at a desired molarratio, generally in the range of approximately 1:100 to 100:1, typicallyabout 1:10 to 10:1, preferably about 1:2 to 2:1. Alternatively, theuncharged catalyst may be combined with at least one salt[M^(z+)]z[X^(A)]⁻, thereby forming the desired salt via ion exchange. Awide variety of salts may be used for this latter purpose, and thecation M^(+z) can be virtually any cation, although z is generally 1, 2or 3. Suitable M elements are typically chosen from Groups 2 to 13 ofthe Periodic Table of the Elements, but M may also be a polyatomiccation such as the ammonium ion NH₄ ⁺. It should also be noted that thesalt form of the catalyst can be prepared with two or more differentBrønsted acids or metal salts, thereby forming a mixture of salts, i.e.,salts containing different anions [X^(A)]⁻.

[0055] The product of the catalyzed aldol coupling reaction of theinvention depends, of course, on the particular aldehyde reactant(s) andthe specific catalyst used. In one embodiment, the only reactant is anenolizable aldehyde, and the aldol coupling reaction can proceed so asto dimerize the aldehyde, trimerize the aldehyde, or polymerize thealdehyde. Any enolizable aldehyde may be employed, meaning that the solerequirement of the aldehyde is that the α-carbon contain a singleenolizable hydrogen atom. The α-carbon may be substituted with one ortwo nonhydrogen substituents that may be the same or different, e.g., ahydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl,substituted heteroatom-containing hydrocarbyl, or functional group.Preferred enolizable aldehydes contain one substituent at the α-carbonand have the structure of formula (I)

[0056] wherein R¹ is selected from hydrocarbyl, substituted hydrocarbyl,heteroatom-containing hydrocarbyl, substituted heteroatom-containinghydrocarbyl, and functional groups, and is preferably selected fromC₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₆-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl. Optimally, R¹ is selected from C₁-C₁₂ alkyl, substitutedC₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, substituted C₁-C₁₂ heteroalkyl, C₅-C₁₄aryl, substituted C₅-C₁₄ aryl, C₃-C₁₄ heteroaryl, substituted C₃-C₁₄heteroaryl, C₆-C₁₆ aralkyl, substituted C₆-C₁₆ aralkyl, C₃-C₁₆heteroaralkyl, and substituted C₃-C₁₆ heteroaralkyl.

[0057] Typically, a more acidic catalyst, e.g., proline, will result indimerization, while a less acidic catalyst, e.g., an imidazolidinone offormula (VIIA) or (VIIB), will result in trimerization. These reactionsare illustrated in Schemes 3 and 4, below:

[0058] In the above schemes, “Me” represents methyl, “Ph” representsphenyl, and “TCA” represents trichloroacetic acid (such that thecatalyst shown in Scheme 4 is in the form of the trichloroacetate salt).Specific reactions of Schemes 3 and 4, wherein R¹ is methyl (such thatthe enolizable aldehyde is propionaldehyde), are described in Examples 1and 8.

[0059] It will be appreciated that the tetrahydropyran (VIII) and theβ-hydroxy aldehyde (IX) may be subjected to further reaction, dependingupon the ultimate product desired. The further reaction may, in mostcases, be carried out in the context of a “one-pot synthesis,” withoutisolation or purification of (VIII) or (IX). Examples of furtherreactions that may be carried out to modify reaction products (VIII) and(IX) include reduction with a suitable reducing agent (e.g., sodiumborohydride) to convert carbonyl moieties to hydroxyl groups,hydrogenation in the presence of an alcoholic acid (e.g., CSA inmethanol) to convert hydroxyl groups to ethers, additional aldolcoupling reactions with aldehydes or ketones, and the like.

[0060] In another embodiment, the aldol coupling reaction is carried outwith an enolizable aldehyde as described above, e.g., having thestructure of formula (I), and an additional aldehyde, such that aldolcoupling is a “cross-aldol” reaction in which the α-carbon of theenolizable aldehyde undergoes nucleophilic addition to the carbonylcarbon of the additional aldehyde. The second aldehyde may or may not beenolizable, and is generally represented by formula (II)

[0061] in which R² is selected from hydrocarbyl, substitutedhydrocarbyl, heteroatom-containing hydrocarbyl, and substitutedheteroatom-containing hydrocarbyl, and is preferably selected fromC₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₆-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, and is most preferably selected from C₁-C₁₂ alkyl,substituted C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, substituted C₁-C₁₂heteroalkyl, C₅-C₁₄ aryl, substituted C₅-C₁₄ aryl, C₃-C₁₄ heteroaryl,substituted C₃-C₁₄ heteroaryl, C₆-C₁₆ aralkyl, substituted C₆-C₁₆aralkyl, C₃-C₁₆ heteroaralkyl, and substituted C₃-C₁₆ heteroaralkyl.

[0062] These aldol coupling reactions involving two or more nonidenticalaldehydes are illustrated in the schemes below. Schemes 5 and 6 showaldol coupling reactions of the invention wherein one of the aldehydereactants is enolizable and the second is nonenolizable (whereinapproximately one equivalent of each aldehyde is employed in Scheme 5,and two equivalents of the nucleophilic aldehyde are employed in Scheme6), and Scheme 7 illustrates an aldol coupling reaction of the inventionusing two enolizable aldehyde reactants.

[0063] A reaction encompassed by Scheme 5, in which aldol couplinginvolves the addition of propionaldehyde to benzaldehyde (i.e., R¹ ismethyl), is described in Example 4. A reaction analogous to that ofScheme 6 is described in Example 9. A reaction of Scheme 7, whereinaldol coupling involves the addition of propionaldehyde toisovaleraldehyde, both enolizable aldehydes, is described in Example 5.As indicated above, further reactions may be carried out to modify theβ-hydroxy aldehydes (X) and (XI) as desired.

[0064] As documented in the examples, aldol coupling reactions ofaldehydes in the presence of nonmetallic, chiral organic catalysts asdescribed herein proceed in a synthetically straightforward manner withexcellent levels of enantioselectivity.

[0065] The method of the invention may be applied to the synthesis ofsaccharides or analogs thereof, including monosaccharides,disaccharides, and polysaccharides. In this embodiment, the aldolcoupling reaction is carried out with at least one enolizable aldehydeof formula (I) wherein R¹ is a protected hydroxyl, sulfhydryl, or aminogroup, typically a protected hydroxyl group. Suitable protecting groupswill be known to those of ordinary skill in the art and are described inthe pertinent texts and literature; see Greene, supra. Non-limitingexamples of hydroxyl-protecting groups useful in this embodimentinclude, without limitation: silyl moieties, such as trialkylsilyl(e.g., triisopropylsilyl, or “TIPS”; trimethylsilyl, or “TMS”) moieties,which form silyl ethers; benzyl (“Bn”) and substituted benzyl moietiessuch as p-methoxybenzyl (“PBN”), which form benzyl ethers; and acylmoieties, such as acetyl, which form esters, such as acetyl (“Ac”)groups.

[0066] For example, trimerization of O-protected hydroxyaldehyde willgive rise to the tetrahydropyran of formula (VIII) wherein R¹ isprotected hydroxyl (—O—Pr where Pr is a protecting group), whichcorresponds to a protected glucose molecule:

[0067] The protecting groups may be removed using conventional reagentsand methods to give the unprotected monosaccharide. Trimerization usingtwo different aldehydes H—(CO)—CH₂—Pr¹ and H—(CO)—Pr²— where Pr¹ and Pr²are orthogonally removable protecting groups such as benzyl andacetyl—will result in a bis-differentially protected glucose molecule,where further reactions may then be conducted by removing one but notboth protecting groups and reacting the initially unprotected group(s)prior to removal of the second protecting group.

[0068] Any of the reactions herein can be carried out on a solidsupport, using solid phase synthesis techniques. Solid-phase synthesisenables implementation of the present aldol coupling reaction incombinatorial chemistry processes, wherein an array or “matrix” ofreactions are conducted in parallel on a single substrate. In such acase, the catalyst itself can be bound either directly or indirectly tothe surface of a solid substrate, if indirectly, through a cleavable ornoncleavable linker. For example, the catalyst of formula (VIIA) or(VIIB) can be linked to the surface of a substrate through any of R⁸,R¹³, or R¹⁶ through R¹⁷. Any solid support may be used. Typicalsubstrates are those conventionally used in solid phase chemistry andwhich allow for chemical synthesis thereon. The only limitation upon thematerials useful for constructing substrates is that they must becompatible with the reaction conditions to which they are exposed.Suitable substrates useful in practicing the methods of the inventioninclude, but are not limited to, organic and inorganic polymers (e.g.,polyethylene, polypropylene, polystyrene, polytetrafluoroethylene),metal oxides (e.g., silica, alumina), mixed metal oxides, metal halides(e.g., magnesium chloride), minerals, quartz, zeolites, and the like.Other substrate materials will be apparent to those of skill in the art.

[0069] Process conditions: The catalytic aldol coupling reactions of theinvention are generally carried out in a solvent, typically a nonpolarorganic solvent, although the specific solvent will depend, of course,on the nature of the reactants, i.e., on any substituents present on thealdehyde(s). Ideally, the solvent selected allows retention andregeneration of the catalyst and removal of the reaction productfollowing completion of the reaction. Examples of suitable solventsinclude, without limitation, benzene, chloroform, ethyl acetate,tetrahydrofuran, dioxane, acetonitrile, dimethylsulfoxide,N-methylpyrrolidone, and dimethyl formamide. The aldol coupling reactionmay be carried out in batch, semi-continuously or continuously, in airor an inert atmosphere, at autogenous pressure or higher, depending, forexample, on the nature of the catalyst composition and reactants used.The reaction temperature will generally be in the range of about −100°C. to 100° C., preferably in the range of about −90° C. to 50° C. Lowertemperatures, in the range of about 0° C. to about 10° C., generallyresult in a higher yield and greater enantioselectivity.

[0070] The amount of catalyst is generally in the range of about 0.1mole % to 1 stoichiometric equivalent, preferably in the range of about1 mol % to 20 mole %, and the molar ratio of the aldehydes within thereaction mixture will depend on the desired product. For most couplingreactions, wherein a straightforward coupling is desired between two ormore aldehydes, approximately one equivalent of each aldehyde will beused. Industrially, the reaction may be scaled up to 10,000 gallons ormore. Catalysis may be heterogeneous or homogeneous. It will beappreciated by those skilled in the art of catalysis that theaforementioned process conditions may vary depending on the particularreaction, the desired product, the equipment used, and the like.Generally, the reaction product is obtained after completion of thereaction, wherein an optional extraction and/or catalyst recovery stepand/or drying is followed by concentration or distillation to give thecrude product and purification, e.g., by chromatography, sublimation,precipitation, extraction, crystallization with optional seeding and/orco-crystallization aids. Alternatively, the reaction product—e.g., aβ-hydroxy aldehyde—may be immediately subjected to further reactionwithout first being isolated and purified.

[0071] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, that the description above as well as the examples that followare intended to illustrate and not limit the scope of the invention.Other aspects, advantages and modifications within the scope of theinvention will be apparent to those skilled in the art to which theinvention pertains.

[0072] All patents, patent applications, journal articles and otherreference cited herein are incorporated by reference in theirentireties.

[0073] Experimental

[0074] In the following examples, efforts have been made to ensureaccuracy with respect to numbers used (e.g., amounts, temperature, etc.)but some experimental error and deviation should be accounted for.Unless indicated otherwise, temperature is in degrees C. and pressure isat or near atmospheric.

[0075] Commercial reagents were purified prior to use following theguidelines of Perrin and Armarego, Purification of Laboratory Chemicals,Fourth Edition (Oxford, Butterworth-Heinemann, 1996). Dimethylformamidewas obtained from EM Science in a DriSolv™ container and used assupplied. Nonaqueous reagents were transferred under nitrogen orcannula. Organic solutions were concentrated under reduced pressure on aBüchi rotary evaporator using an ice-water bath. Chromatographicpurification of products was accomplished using forced-flowchromatography on ICN 60 32-64 mesh silica gel 63 according to themethod of Still et al. (1978) J. Org. Chem. 43:2923. Thin-layerchromatography (TLC) was performed on EM Reagents 0.25 mm silica gel60-F plates. Visualization of the developed chromatogram was performedby fluorescence quenching or by anisaldehyde stain. Known catalyst((5S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one and(2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one, respectively)was prepared as described in U.S. Pat. No. 6,369,243 to MacMillan et al.

[0076]¹H and ¹³C NMR spectra were recorded on a Mercury 300 spectrometer(300 MHz and 75 MHz), and are internally referenced to residual protiosolvent signals. Data for ¹H NMR are reported as follows: chemical shift(δ ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, br=broad), coupling constant (Hz), integration andassignment. Data for ¹³C NMR are reported in terms of chemical shift (δppm). IR spectra were recorded on a Perkin Elmer Paragon 1000spectrometer and are reported in terms of frequency of absorption(cm⁻¹). Mass spectra were obtained from the UC Irvine Mass Spectralfacility. Gas liquid chromatography (GLC) was performed onHewlett-Packard 6850 and 6890 Series gas chromatographs equipped with asplit-mode capillary injection system and flame ionization detectorsusing a Bodman Chiraldex β-DM (30 m×0.25 mm) column or an ASTECChiraldex γ-BP (30 m×0.25 mm) as noted. High performance liquidchromatography (HPLC) was performed on Hewlett-Packard 1100 Serieschromatographs using a Chiralcel AD column (25 cm) or a Chiralcel OJcolumn (25 mm) and OJ guard (5 cm) as noted. Optical rotations weretaken using a Jasco P-1010 polarimeter (WI lamp, 589 nm, 25° C.).

[0077] Examples 1 through 11 describe the use of the chiral organiccatalysts L-proline and(2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one in catalyzingthe direct and enantioselective aldol coupling reaction of aldehydesubstrates.

EXAMPLE 1

[0078] Synthesis of (2S, 3S)-3-hydroxy-2-methylpentanal (Table 1, entry1): A suspension of freshly distilled propionaldehyde (3.61 mL, 50 mmol)and l-proline in 25.0 mL of dimethylformamide was stirred at 4° C. for10 h. The resulting solution was diluted with diethyl ether and washedsuccessively with water and brine. The combined aqueous layers wereback-extracted with 3 portions of dichloromethane. The organic layerswere combined, dried over anhydrous MgSO₄, and concentrated in vacuo.Flash chromatography (5:2 pentane:diethyl ether) afforded the titlecompound as a clear, colorless oil in 80% yield (2.31 g, 20 mmol), 99%ee, and 4:1 anti:syn. Analytical data for this compound are identical inevery respect to previously reported values (Mahrwald (1998) Synthesis,262), with the exception of optical rotation which has not beenreported. [α]D=−14.7 (c=1.0, CHCl3). The product ratios were determinedby GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol,obtained by the method of Yamamoto (Furuta et al. (1989) J. Org. Chem.54:1481), using a Bodman Chiraldex γ-DM (30 m×0.25 mm) column (110° C.isotherm, 23 psi); (2S, 3S) anti isomer tr=24.6 min, (2R, 3R) antiisomer tr=25.5 min, (2R, 3S) and (2S, 3R) syn isomers tr=22.4 min.

EXAMPLE 2

[0079] Synthesis of (2S, 3S)-3-hydroxy-2,5-dimethylhexanal (Table 1,entry 2): A solution of freshly distilled propionaldehyde (144 μL, 2.0mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowlyover the course of 2.5 h to a stirring suspension of isovaleraldehyde(107 μL, 1.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μLdimethylformamide at 4° C. After 16 h, the resulting solution wasdiluted with diethyl ether and washed successively with water and brine.The combined aqueous layers were back-extracted with 3 portions ofdichloromethane. The organic layers were combined, dried over anhydrousMgSO₄, and concentrated in vacuo. Flash chromatography (20:7pentane:diethyl ether) afforded the title compound as a clear, colorlessoil in 88% yield (126 mg, 0.88 mmol), 97% ee and 3:1 anti:syn. IR (film)3419, 2958, 2935, 2872, 1719,1466, 1368, 1152, 1098, 1062,1025, 976.5cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ9.75 (d, J=1.5 Hz, 1H, CHO); 3.89 (ddd,1H, J=9.9, 6.6, 2.7 Hz, 1H, CHOH); 2.44 (m, 1H, CHCH₃); 1.83 (m, 1H,CH(CH₃)₂); 1.47 (m, 1H, CH₂); 1.26 (m, 1H, CH₂); 1.14 (d, 3H, J=7.2 Hz,CH₃CHCHO); 0.97 (d, 3H, J=5.1 Hz, (CH₃)₂CH); 0.92 (d, 3H, J=6.6 Hz,(CH₃)₂CH); ¹³C NMR (75 MHz, CDCl₃) δ205.5, 70.9, 52.8, 44.0, 34.5, 24.1,21.8, 11.1; HRMS (CI) exact mass calcd for [M +H]⁺ (C₈H₁₇O₂) requiresm/z 145.1228, found m/z 145.1225; [α]_(D)=−33.6 (c=1.0, CHCl₃). Theproduct ratios were determined by GLC analysis of the acetal derivedfrom 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto,supra) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (100° C.isotherm, 23 psi); (2S, 3S) anti isomer t_(r)=50.8 min, (2R, 3R) antiisomer t_(r)=53.2 min, (2R, 3S) and (2S, 3R) syn isomers t_(r)=45.5 min.

EXAMPLE 3

[0080] Synthesis of (2S, 3S)-3-cyclohexyl-3-hydroxy-2-methylpropanal(Table 1, entry 3): A solution of freshly distilled propionaldehyde (72μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was addedslowly over the course of 20 h to a stirring suspension of cyclohexanecarboxaldehyde (242 μL, 2.0 mmol), L-proline (11.5 mg, 0.10 mmol) and500 μL dimethylformamide at 4° C. After 22 hours, the resulting solutionwas diluted with diethyl ether and washed successively with water andbrine. The combined aqueous layers were back-extracted with 3 portionsdichloromethane. The organic layers were combined, dried over anhydrousMgSO₄, and concentrated in vacuo. Flash chromatography (20:7pentane:diethyl ether) afforded the title compound as a clear, colorlessoil in 87% yield (148 mg, 0.87 mmol), 99% ee and 93:7 anti:syn. IR(film) 3438, 2928, 2853, 1722, 1450, 1396, 1376, 1314, 1186, 1112, 1063,975.8, 893.2, 847.5 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ9.75 (d, 1H, J=2.1Hz, CHO); 3.53 (dd, 1H, J=7.2, 4.8 Hz, CHOH); 2.58 (m, 1H, CHCH₃);1.8-1.0 (br m, 11H, cyclohexyl); 1.10 (d, 3H, J=7.2 Hz, CH₃); ³C NMR (75MHz, CDCl₃) δ206.1, 77.1, 49.2, 40.7, 30.3, 26.73, 26.69, 26.68, 26.4,11.4; HRMS (CI) exact mass calcd for [M+H]₊ (C₁₀H₁₉O₂) requires m/z171.1385, found m/z 171.1386. [α]_(D)=−5.1 (c=1.0, CHCl₃). The productratios were determined by GLC analysis of the corresponding4-cyclohexyl-2,2,5-trimethyl-[1,3]dioxane (obtained by NaBH₄ reductionfollowed by acetonide protection of the 1,3-diol according to the methodof Goto, in Kitamura et al. (1984) J. Am. Chem. Soc. 106:3252) using aBodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi);(2S, 3S) anti isomer t_(r)=17.8 min, (2R, 3R) anti isomer t_(r)=18.7min, (2R, 3S) and (2S, 3R) syn isomers t_(r)=21.0, 22.2 min.

[0081] Stereochemical analysis: The absolute stereochemistry of (2S,3S)-3-Cyclohexyl-3-hydroxy-2-methylpropanal was determined bycorrelation to (2S, 3S)-3-cyclohexyl-3-hydroxy-2-methylpropionic acidmethyl ester, as follows. A stirring solution of (2S,3S)-3-cyclohexyl-3-hydroxy-2-methylpropanal (77 mg, 0.45 mmol) in 3.0 mLof ethanol was treated sequentially with a solution of AgNO₃ (123 mg,0.73 mmol) in 2.0 mL of water and a solution of NaOH (123 mg, 3.1 mmol)in 3.0 mL of 2:1 ethanol:water. After stirring for 4 hours, the mixturewas filtered through celite, and the filter cake was rinsed with severalportions of ethyl acetate. The filtrate was then washed with 1N HCl andthe aqueous layer was back-extracted with ethyl acetate. The combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The residue was then dissolved in 8.0 mL ofmethanol and trimethylsilyldiazomethane (2.0 M in hexane) was addeduntil a yellow color persisted. Excess diazomethane was quenched by thedropwise addition of acetic acid. The resulting colorless solution wasthen diluted with ether, washed successively with 10% NaHCO₃ and brine,dried over anhydrous MgSO₄, and concentrated in vacuo. Flashchromatography (5-10% ethyl acetate in hexanes, linear gradient)afforded a 71% yield (63 mg, 0.32 mmol) of (2S,3S)-3-cyclohexyl-3-hydroxy-2-methylpropionic acid methyl ester;[α]_(D)=+5.1 (c=1.05, CHCl₃) (lit.[α]_(D)=−8.1 (c=1.05, CHCl₃) for (2R,3R)-3-cyclohexyl-3-hydroxy-2-methylpropionic acid methyl ester; Meyerset al. (1981) J. Am. Chem. Soc. 103:4278).

EXAMPLE 4

[0082] Synthesis of (2S, 3S)-3-hydroxy-2-methyl-3-phenyl-propionaldehyde(Table 1, entry 4): A solution of freshly distilled propionaldehyde (72μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was addedslowly over the course of 16 h to a stirring suspension of benzaldehyde(1.02 mL, 10 mmol), L-proline (11.5 mg, 0.10 mmol) and 4.5 mLdimethylformamide at 4° C. After 16 hours, the resulting solution wasdiluted with ethyl acetate and washed successively with water and brine.The combined aqueous layers were back-extracted with 3 portions ofdichloromethane. The organic layers were combined, dried over anhydrousNa₂SO₄, and then concentrated. Flash chromatography (4:1 hexanes:ethylacetate) afforded the title compound as a clear, colorless oil in 81%yield (132 mg, 0.81 mmol), 99% ee and 3:1 anti:syn. Analytical data forthis compound are identical in every respect to that previously reported(Mahrwald, supra) with the exception of optical rotation which has notbeen reported. [α]_(D)=+9.1 (c=1.0, CHCl₃). The product ratios weredetermined by HPLC analysis of the corresponding alcohol (obtained byNaBH₄ reduction) using a Chiracel AD and AD guard column (1.0%isopropanol/hexanes, 1 mL/min); (2S, 3S) anti isomer t_(r)=147.5 min,(2R, 3R) anti isomer t_(r)=161.1 min, (2R, 3S) and (2S, 3R) syn isomerst_(r)=173.0, 200.0 min.

EXAMPLE 5

[0083] (2S, 3S)-3-hydroxy-2,4-dimethylpentanal (Table 1, entry 5). Asolution of freshly distilled propionaldehyde (1.81 mL, 25.0 mmol) in12.5 mL dimethylformamide pre-cooled to 4° C. was added slowly over thecourse of 20 h to a stirring suspension of isobutyraldehyde (4.54 mL, 50mmol), L-proline (288 mg, 2.5 mmol) and 12.5 mL dimethylformamide at 4°C. After 30 h, the resulting solution was diluted with diethyl ether andwashed successively with water and brine. The combined aqueous layerswere back-extracted with 3 portions of dichloromethane. The organiclayers were combined, dried over anhydrous MgSO₄, and concentrated invacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded thetitle compound as a clear, colorless oil in 82% yield (2.65 g, 20.6mmol), >99% ee and 96:4 anti:syn. Analytical data for this compound areidentical in every respect to the previously reported values (Mahrwald,supra), with the exception of optical rotation which has not beenreported. [α]_(D)=−17.9 (c=1.0, CHCl₃). The product ratios weredetermined by GLC analysis of the acetal derived from2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto) usinga Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23psi); (2S, 3S) anti isomer t_(r)=31.8 min, (2R, 3R) anti isomert_(r)=33.9 min, (2R, 3S) and (2S, 3R) syn isomers t_(r)=29.4, 29.8 min.

[0084] Stereochemical analysis: The absolute stereochemistry of (2S,3S)-3-hydroxy-2,4-dimethylpentanal was determined by correlation to (2S,3S)-3-hydroxy-2,4-dimethylpentanoic acid methyl ester, as follows. Astirring solution of (2S, 3S)-3-hydroxy-2,4-dimethylpentanal (101 mg,0.63 mmol) in 3.0 mL of ethanol was treated sequentially with a solutionof AgNO₃ (170 mg, 1.0 mmol) in 2.0 mL of water and a solution of NaOH(171 mg, 4.3 mmol) in 3.0 mL of 2:1 ethanol:water. After stirring for 4hours, the mixture was filtered through celite, and the filter cake wasrinsed with several portions of ether. The filtrate was then washed with1N HCl and the aqueous layer was back-extracted with ether. The combinedorganic extracts were dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue was then dissolved in 8.0 mL ofmethanol, and trimethylsilyldiazomethane (2.0 M in hexane) was addeduntil a yellow color persisted. Excess diazomethane was quenched by thedropwise addition of acetic acid. The resulting colorless solution wasthen diluted with ether, washed successively with 10% NaHCO₃ and brine,dried over anhydrous MgSO₄, and concentrated in vacuo. Flashchromatography (5-25% ether in pentane, linear gradient) afforded a 39%yield (47 mg, 0.25 mmol) of (2S, 3s)-3-hydroxy-2,4-dimethylpentanoicacid methyl ester; [α]_(D)=+7.6 (c=0.85, CHCl₃) (lit.[α]_(D)=+11.1(c=0.85, CHCl₃; Oppolzer et al. (1991) Tet. Lett. 32:61).

EXAMPLE 6

[0085] Synthesis of (2S)-2-[(1S)-1-hydroxy-2-methylpropyl]hexanal (Table1, entry 6): A solution of freshly distilled hexanal (120 μL, 1.0 mmol)in 500 μL dimethylformamide was added slowly over the course of 24 h toa stirring suspension of isobutyraldehyde (272 μL, 3.0 mmol), L-proline(11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at room temperature.After 24 h, the resulting solution was diluted with diethyl ether andwashed successively with water and brine. The combined aqueous layerswere back-extracted with 3 portions dichloromethane. The organic layerswere combined, dried over anhydrous MgSO₄, and concentrated in vacuo.Flash chromatography (7:3 pentane:diethyl ether) afforded the titlecompound as a clear, colorless oil in 80% yield (127 mg, 0.80 mmol), 98%ee and 96:4 anti:syn. IR (film) 3458, 2960, 2934, 2874, 2725, 1720,1467, 1328, 1220, 1146, 1024, 991.2, 959.9, 901.1, 775.6 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ9.75 (d, 1H, J=3.3 Hz, CHO); 3.56 (dd (apparent q),1H, J=6.0, 5.7 Hz, CHOH); 2.46 (dddd, 1H, J=8.4, 5.7, 5.7, 3.3 Hz,CHCH₂); 1.99 (d, 1H, J=6.0 Hz, OH); 1.82 (m, 1H, CH(CH₃)₂); 1.70 (m, 1H,CHCH₂); 1.58 (m, 1H, CHCH₂); 1.30 (m, 4H, CH₂CH₂CH3); 0.97 (d, 3H, J=6.6Hz, CH(CH₃)₂); 0.93 (d, 3H, J=6.6 Hz, CH(CH₃)₂); 0.90 (dd (apparent t),3H, J=6.6, 6.6 Hz); ¹³C NMR (75 MHz, CDCl₃) δ206.1, 76.7, 54.9, 31.3,29.5, 26.7, 23.2, 20.0, 17.1, 14.2; HRMS (CI) exact mass calcd for[M+H]⁺ (C₁₀H₂₁O₂) requires m/z 173.1541, found m/z 173.1540;[α]_(D)=−15.4 (c=1.0, CHCl₃). The product ratios were determined by GLCanalysis of the acetal derived from 2,2-dimethylpropane-1,3-diol(obtained by the method of Yamamoto, supra) using a Bodman Chiraldexβ-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S, 3S) antiisomer t_(r)=97.8 min, (2R, 3R) anti isomer t_(r)=102.7 min, (2R, 3S)and (2S, 3R) syn isomers t_(r)=94.4, 96.5 min.

EXAMPLE 7

[0086] Synthesis of (2S, 3S)-2-benzyl-3-hydroxy-4-methylpentanal (Table1, entry 7): A solution of freshly distilled hydrocinnamaldehyde (132μL, 1.0 mmol) in 500 μL dimethylformamide was added slowly over thecourse of 24 h to a stirring suspension of isobutyraldehyde (272 μL, 3.0mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide atroom temperature. After 26 h, the resulting solution was diluted withethyl acetate and washed successively with water and brine. The combinedaqueous layers were back-extracted with 3 portions dichloromethane. Theorganic layers were combined, dried over anhydrous Na₂SO₄, andconcentrated in vacuo. Flash chromatography (3:1 hexanes:ethyl acetate)afforded the title compound as a clear, colorless oil in 75% yield (155mg, 0.75 mmol), 91% ee and 95:5 anti:syn. IR (film) 3466, 3086, 3063,3028, 2962, 2932, 2834, 2733, 1950, 1875, 1806, 1722, 1604, 1496, 1454,1390, 1368, 1244, 1180, 1136, 1049, 1031, 993.0, 964.3, 849.7, 800.6,739.8, 700.2 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ9.83 (d, 1H, J=2.1 Hz, CHO);7.27 (m, 5H, Ar—H); 3.43 (ddd, 1 H, J=6.6, 6.6, 4.5 Hz, CHOH); 3.06 (dd,1H, J=13.2, 7.8 Hz, PhCH₂); 2.92 (dd, 1H, J=13.2, 6.9 Hz, PhCH₂); 2.81(m, 1H, CHCH₂); 2.15 (d, 1H, J=6.0 Hz, OH); 1.90 (m, 1H, CH(CH₃)₂); 0.96(d, 3H, J=6.6 Hz, CH(CH₃)₂); 0.92 (d, 3H, J=7.2 Hz, CH(CH₃)₂); ¹³C NMR(75 MHz, CDCl₃) δ205.6, 129.2, 128.9, 128.6, 126.8, 76.9, 55.8, 33.4,32.0, 19.7, 18.2; HRMS (CI) exact mass calcd for [M+H]⁺ (C₁₃H₁₉O₂)requires m/z 207.1385, found m/z 207.1386; [α]_(D)=−7.9 (c=1.0, CHCl₃).The product ratios were determined by HPLC analysis of the correspondingalcohol (obtained by NaBH₄ reduction) using a Chiracel OJ and OJ guardcolumn (1.0% ethanol/hexanes, 1 mL/min); (2S, 3S) anti isomer t_(r)=7.5min, (2R, 3R) anti isomer t_(r)=9.4 min, (2R, 3S) and (2S, 3R) synisomers t_(r)=6.3, 6.9 min.

[0087] The conditions, yield, and enantioselectivity for the reactionsof Examples 1 through 7 are summarized in Table 1: TABLE 1

entry R¹ R² Product % yield anti:syn % ee 1 Me Et

80  4:1 99 2 Me i-Bu

88  3:1 97 3 Me c-C₆H₁₁

87 14:1 99 4 Me Ph

81  3:1 99 5 Me i-Pr

82 24:1 >99 6 n-Bu i-Pr

80 24:1 98 7 Bn i-Pr

75 19:1 91

[0088] As demonstrated by the data in Table 1, addition ofpropionaldehyde, as an aldehyde donor, to a series of aldehyde acceptorsin the presence of the amine catalyst provided excellent yields of thedesired cross-aldol product. The data also demonstrate thatpropionaldehyde can be used as an aldol nucleophile with a broad rangeof aldehyde acceptors, including both alkyl- and aryl-substituted.

[0089] Entry 2, representing the addition of propionaldehyde toisovaleraldehyde, indicates that the reaction product was obtained in88% yield and 97% ee. This indicates that the method of the invention isable to provide a single regioisomer despite the fact that both thealdol donor and accept bear enolizable α-methylene protons. Entries 5-7,corresponding to Examples 5-7, indicate that the aldol reaction cantolerate a range of structural variation in the aldehyde donor (R¹=Me,n-Bu, Bn, 19:1 to 24:1 anti:syn, 91 to >99% ee). In contrast to prolinemediated ketone additions, lower catalyst loadings (10 mol %) andshorter reaction times (11 to 26 hours) were possible without loss inreaction efficiency (Hajos et al. (1974) Org. Chem. 39:1615; Eder et al.(1971) Angew. Chem. 10:496; Agami et al. (1987) Bull. Chim. Soc. Fr.2:358). Entry 5 also illustrates the preparative utility of thereaction, insofar as the addition of propionaldehyde to isobutyraldehydewas performed on a 25 mmol scale to afford 2.65 g (82% yield) of(2S,3S)-3-hydroxy-2,4-dimethylpentanal in >99% ee with 24:1anti-diastereoselectivity.

EXAMPLE 8

[0090] Synthesis of (2R, 3R, 4S, 5S,6R)-6-ethyl-3,5-dimethyltetrahydro-2H-pyran-2,4-diol:

[0091] Propionaldehyde (108 μL, 1.5 mmol) was added to a solution of(2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (24.6 mg, 0.10mmol) and trichloroacetic acid (16.0 mg, 0.10 mmol) in 500 μL dioxanepre-cooled to +4° C. After stirring for 12 hours, a portion of thereaction mixture was withdrawn, diluted with CH₂C₁₂, washed with water,brine, dried over anhydrous Na₂SO₄, and concentrated to afford the titlecompound in 94% ee and 12:1 d.r. as a 1:1 mixture of anomers at C-2. IR(film) 3419, 2968, 2938, 2881, 2731, 1686, 1636, 1465, 1412, 1376, 1351,1323, 1276, 1242, 1152, 1118, 1087, 1045, 1021, 1005, 972.4 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ5.16-4.93 (m, 1H, OCHOH); 4.56-4.49 (m, 1H, CH₂CH);3.95, 3.60, 3.44, 3.14 (m, 1H, CHCHCHOH); 1.84-1.30 (m, 4H, CH₂, and 2CHCH₃); 1.01-0.82 (m, 9H, 3 CH₃); ¹³C NMR (75 MHz, CDCl₃) δ101.0, 100.3,99.8, 97.5, 96.7, 95.5, 94.8, 94.4, 81.8, 80.3, 77.5, 75.4, 41.7, 38.4,36.9, 35.5, 28.1, 28.0, 25.9, 25.7, 25.4, 25.3, 12.5, 11.7, 10.7, 10.2,10.1, 9.9, 9.6, 8.9, 8.7, 8.6, 4.3. Product ratios were determined byGLC analysis of the 2-acetoxy derivative (Ac₂O (3.0 equiv.), pyridine(10.0 equiv), in CH₂C₁₂ (1.0 M), r.t. 2.5 h) on an ASTEC Chiraldex γ-BP(30 m×0.25 mm) column. (90° C. isotherm, 23 psi); (2R, 3R, 4S, 5S, 6R)isomer t_(r)=38.3 min, (2S, 3R, 4S, 5S, 6R) isomer t_(r)=47.0 min, (2S,3S, 4R, 5R, 6S) isomer t_(r)=39.4 min, (2R, 3S, 4R, 5R, 6S) isomert_(r)=54.5 min, (2R, 3R, 4R, 5S, 6R) isomer t_(r)=49.9 min, (2S, 3R, 4R,5S, 6R) isomer t_(r)=52.3 min, (2S, 3S, 4S, 5R, 6S) isomer t_(r)=40.5min, (2R, 3S, 4S, 5R, 6S) isomer t_(r)=45.7 min.

EXAMPLE 9

[0092] Synthesis of 2,4-dimethyl-1-(4-nitro-phenyl)-pentane-1,3,5-triol:

[0093] The method of Example 4 was carried out substantially asdescribed using the catalyst of Example 8, substituting4-nitrobenzaldehyde for benzaldehyde and using two equivalents ofpropionaldehyde, giving3,5-dihydroxy-2,4-dimethyl-5-(4-nitro-phenyl)-pentanal as the reactionproduct.

[0094] This dihydroxy aldehyde was then reduced with sodium borohydrideto give the desired product

[0095] in 74% yield, 89% ee, and 13:1 (anti:syn:syn).

EXAMPLE 10

[0096] Synthesis of 2,4,6-tri-O-benzyl-D-glucopyranose:

[0097] Freshly distilled benzyloxyacetaldehyde (150 mg, 1.0 mmol) wasadded to a stirring solution of(2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-onetrichloroacetate (27.3 mg, 67 μmol) in diethyl ether (330 μL, 3.0 M) at−20° C. After complete consumption of the starting material wasdetermined by TLC analysis (24 h), the reaction mixture was diluted withethyl acetate, washed with saturated NH₄Cl, brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. Flash chromatography (19:1dichloromethane:diethyl ether)afforded the title compound as a clear,colorless oil in 85% yield (104 mg, 0.69 mmol), 95% ee, and 11:1 dr. ¹HNMR (300 MHz, CDCl₃) δ7.31 (m, 15H, Ar—H), 5.38 (m, 1H, OCHO), 4.83 (m,1H, CHCH₂), 4.55 (br, m, 5H), 4.12 (br m, 1H, 3.64 (br m, 4H, CHO), 3.30(m, 1H, CHO); ¹³C NMR (75 MHz, CDCl₃) δ(α-anomer) 90.4 (C-1), 74.6(C-3), and 68.9 (C-6); (β-anomer) 97.3 (C-1), 76.9 (C-3), 69.2 (C-6),which is consistent with previously reported values (Ito et al. (1980)Carbohydrate Res. 86:193).

EXAMPLE 11

[0098] Synthesis of 2,4-di-O-benzyl-6-acetoxy-D-glucopyranose: Themethod of Example 10 was repeated substantially as described using threeequivalents of benzyloxyacetaldehyde and one equivalent of O-acetoxyacetaldehyde, to give the bis-differentially protected glucose molecule

[0099] in 65% yield, 93% ee, and 6:1 (anti:syn:syn).

We claim:
 1. A method for carrying out an enantioselective aldolcoupling reaction between aldehyde molecules, comprising contacting (a)an enolizable aldehyde and optionally (b) an additional aldehyde, with(c) a catalytically effective amount of a nonmetallic chiral catalystcontaining a Group 15 or Group 16 heteroatom.
 2. The method of claim 1,wherein the additional aldehyde is present, and the aldol couplingreaction is a cross-aldol reaction in which the α-carbon of theenolizable aldehyde undergoes nucleophilic addition to the carbonylcarbon of the additional aldehyde.
 3. The method of claim 2, wherein theadditional aldehyde is a non-enolizable aldehyde.
 4. The method of claim2, wherein the enolizable aldehyde has the structure of formula (I) andthe additional aldehyde has the structure of formula (II)

in which: R¹ and R² are independently selected from hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, andsubstituted heteroatom-containing hydrocarbyl.
 5. The method of claim 4,wherein R¹ and R² are independently selected from C₁-C₂₄ alkyl,substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substituted C₁-C₂₄heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄ heteroaryl,substituted C₁-C₂₄ heteroaryl, C₆-C₂₄ aralkyl, substituted C₆-C₂₄aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄ heteroaralkyl. 6.The method of claim 5, wherein R¹ and R² are independently selected fromC₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, substitutedC₁-C₁₂ heteroalkyl, C₅-C₁₄ aryl, substituted C₅-C₁₄ aryl, C₃-C₁₄heteroaryl, substituted C₃-C₁₄ heteroaryl, C₆-C₁₆ aralkyl, substitutedC₆-C₁₆ aralkyl, C₃-C₁₆ heteroaralkyl, and substituted C₃-C₁₆heteroaralkyl.
 7. The method of claim 2, wherein the catalyst iseffective to raise the energy level of the highest occupied molecularorbital (HOMO) of the enolizable aldehyde.
 8. The method of claim 2,wherein the heteroatom of the catalyst is selected from the groupconsisting of nitrogen, oxygen, sulfur and phosphorus.
 9. The method ofclaim 8, wherein the heteroatom is nitrogen.
 10. The method of claim 9,wherein the catalyst is a secondary amine or an acid addition saltthereof.
 11. The method of claim 10, wherein the secondary amine ischiral with respect to an axis, plane or center of asymmetry.
 12. Themethod of claim 11, wherein the secondary amine has the structure of(III)

wherein R³ and R⁴ are independently selected from the group consistingof hydrocarbyl, substituted hydrocarbyl, heteroatom-containinghydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or aretaken together to form a ring, such that the amine is a cyclic secondaryamine.
 13. The method of claim 12, wherein R³ and R⁴ are taken togetherto form a 3- to 15-membered, optionally substituted ring.
 14. The methodof claim 13, wherein the secondary amine has the structure of formula(IV)

wherein n is zero or 1, X is a moiety that contains up to 50 atoms andis selected from the group consisting of hydrocarbylene, substitutedhydrocarbylene, heteroatom-containing hydrocarbylene and substitutedheteroatom-containing hydrocarbylene, and X¹ and X² are independentlysubstituted or unsubstituted methylene.
 15. The method of claim 14,wherein the secondary amine has the structure of formula (V)

in which: R⁵, R⁶, R⁷, and R⁸ are independently selected from hydrogen,hydroxyl, sulfhydryl, carboxyl, amino, mono-(C₁-C₂₄ alkyl)-substitutedamino, di-(C₁-C₂₄ alkyl)-substituted amino, mono-(C₅-C₂₄aryl)-substituted amino, di-(C₅-C₂₄ aryl)-substituted amino,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino, C₆-C₂₄arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C5-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or wherein R⁵ and R⁶, and/or R⁷ and R⁸, together form acarbonyl group ═O.
 16. The method of claim 15, wherein X is—(CR⁹R¹⁰)—(X³)_(q)—(CR¹¹R¹²)_(t) and the secondary amine therefore hasthe structure of formula (VI)

in which X³ is O, S, NH, NR¹³, or CR¹⁴R¹⁵, q is zero or 1, t is zero or1, and R⁹, R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁵ are independently selected fromhydrogen, hydroxyl, sulfhydryl, carboxyl, amino,mono-(C₁-C₂₄alkyl)-substituted amino, di-(C₁-C₂₄ alkyl)-substitutedamino, mono-(C₅-C₂₄ aryl)-substituted amino, di-(C₅-C₂₄aryl)-substituted amino, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substitutedamino, C₂-C₂₄ alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino,C₆-C₂₄ arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or wherein R⁹ and R¹⁰, and/or R¹¹ and R¹², together forman oxo moiety ═O; and R¹³ is selected from C₁-C₁₂ hydrocarbyl,substituted C₁-C₁₂ hydrocarbyl, heteroatom-containing C₁-C₁₂hydrocarbyl, and substituted heteroatom-containing C₁-C₁₂ hydrocarbyl.17. The method of claim 16, wherein q is zero, and at least one of R⁵through R⁸ is carboxyl.
 18. The method of claim 17, wherein thesecondary amine is L-proline.
 19. The method of claim 1, wherein theadditional aldehyde is not present.
 20. The method of claim 19, whereinthe aldol coupling reaction comprises dimerization, trimerization, orpolymerization of the enolizable aldehyde.
 21. The method of claim 20,wherein the aldol coupling reaction comprises dimerization of theenolizable aldehyde.
 22. The method of claim 20, wherein the aldolcoupling reaction comprises trimerization of the enolizable aldehyde.23. The method of claim 19, wherein the enolizable aldehyde has thestructure of formula (I)

in which R¹ is selected from hydrocarbyl, substituted hydrocarbyl,heteroatom-containing hydrocarbyl, substituted heteroatom-containinghydrocarbyl, and functional groups.
 24. The method of claim 23, whereinR¹ is selected from C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄heteroalkyl, substituted C₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substitutedC₅-C₂₄ aryl, C₁-C₂₄ heteroaryl, substituted C₁-C₂₄ heteroaryl, C₆-C₂₄aralkyl, substituted C₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, andsubstituted C₂-C₂₄ heteroaralkyl.
 25. The method of claim 24, wherein R¹is selected from C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₁-C₁₂heteroalkyl, substituted C₁-C₁₂ heteroalkyl, C₅-C₁₄ aryl, substitutedC₅-C₁₄ aryl, C₃-C₁₄ heteroaryl, substituted C₃-C₁₄ heteroaryl, C₆-C₁₆aralkyl, substituted C₆-C₁₆ aralkyl, C₃-C₁₆ heteroaralkyl, andsubstituted C₃-C₁₆ heteroaralkyl.
 26. The method of claim 19, whereinthe catalyst is effective to raise the energy level of the highestoccupied molecular orbital (HOMO) of the enolizable aldehyde
 27. Themethod of claim 19, wherein the heteroatom of the catalyst is selectedfrom the group consisting of nitrogen, oxygen, sulfur and phosphorus.28. The method of claim 27, wherein the heteroatom is nitrogen.
 29. Themethod of claim 28, wherein the catalyst is a secondary amine or an acidaddition salt thereof.
 30. The method of claim 29, wherein the secondaryamine is chiral with respect to an axis, plane or center of asymmetry.31. The method of claim 30, wherein the secondary amine has thestructure of (III)

wherein R³ and R⁴ are independently selected from the group consistingof hydrocarbyl, substituted hydrocarbyl, heteroatom-containinghydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or aretaken together to form a ring, such that the amine is a cyclic secondaryamine.
 32. The method of claim 31, wherein R³ and R⁴ are taken togetherto form a 3- to 15-membered, optionally substituted ring.
 33. The methodof claim 32, wherein the secondary amine has the structure of formula(IV)

wherein n is zero or 1, X is a moiety that contains up to 50 atoms andis selected from the group consisting of hydrocarbylene, substitutedhydrocarbylene, heteroatom-containing hydrocarbylene and substitutedheteroatom-containing hydrocarbylene, and X¹ and X² are independentlysubstituted or unsubstituted methylene.
 34. The method of claim 33,wherein the secondary amine has the structure of formula (V)

in which R⁵, R⁶, R⁷, and R⁸ are independently selected from hydrogen,hydroxyl, sulfhydryl, carboxyl, amino, mono-(C₁-C₂₄alkyl)-substitutedamino, di-(C₁-C₂₄alkyl)-substituted amino, mono-(C₅-C₂₄aryl)-substituted amino, di-(C₅-C₂₄ aryl)-substituted amino,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino, C₆-C₂₄arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or wherein R⁵and R⁶, and/or R⁷ and R⁸, together form anoxo moiety ═O.
 35. The method of claim 34, wherein X is—(CR⁹R¹⁰)—(X³)_(q)—(CR¹¹R¹²)_(t) and the secondary amine therefore hasthe structure of formula (VI)

wherein X³ is O, S, NH, NR¹³, or CR¹⁴R¹⁵, q is zero or 1, t is zero or1, and R⁹, R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁵ are independently selected fromhydrogen, hydroxyl, sulfhydryl, carboxyl, amino, mono-(C₁-C₂₄alkyl)-substituted amino, di-(C₁-C₂₄ alkyl)-substituted amino,mono-(C₅-C₂₄ aryl)-substituted amino, di-(C₅-C₂₄ aryl)-substitutedamino, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino, C₆-C₂₄arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or wherein R⁹ and R¹⁰, and/or R¹¹ and R¹², together forman oxo moiety ═O; and R¹³ is selected from C₁-C₁₂ hydrocarbyl,substituted C₁-C₁₂ hydrocarbyl, heteroatom-containing C₁-C₁₂hydrocarbyl, and substituted heteroatom-containing C₁-C₁₂ hydrocarbyl.36. The method of claim 35, wherein q is zero, t is 1, and at least oneof R⁵ through R⁸ is carboxyl.
 37. The method of claim 36, wherein R⁵through R⁷ and R⁹ through R¹² are hydrogen, R⁸ is carboxyl, and thesecondary amine is L-proline.
 38. The method of claim 35, wherein q is1, X³ is NR¹³, t is zero, R⁵ and R⁷ are hydrogen, and R⁶ is —CR¹⁶R¹⁷R¹⁸,such that the secondary amine has the structure of formula (VIIA) or(VIIB)

wherein: R⁸ and R¹³ are as defined previously; and R¹⁶ and R¹⁷ areindependently selected from hydrogen, halo, hydroxyl, C₁-C₁₂hydrocarbyl, substituted C₁-C₁₂ hydrocarbyl, heteroatom-containingC₁-C₁₂ hydrocarbyl, and substituted heteroatom-containing C₁-C₁₂hydrocarbyl; and R¹⁸ is a cyclic group optionally substituted with 1 to4 non-hydrogen substituents and containing zero to 3 heteroatoms. 39.The method of claim 38, wherein: R⁸ has the structure—(L)_(m)—CR¹⁹R²⁰R²¹ wherein m is zero or 1, L is C₁-C₆ alkylene, andR¹⁹, R²⁰ and R²¹ are C₁-C₁₂ hydrocarbyl; R¹³ is C₁-C₁₂ hydrocarbyl; R¹⁶and R¹⁷ are independently selected from hydrogen and C₁-C₁₂ hydrocarbyl;and R¹⁸ is a monocyclic aryl or heteroaryl group optionally substitutedwith 1 to 4 substituents selected from halo, hydroxyl, and C₁-C₁₂hydrocarbyl.
 40. The method of claim 39, wherein: R¹³ is C₁-C₆ alkyl;R¹⁶ and R¹⁷ are hydrogen; R¹⁸ is phenyl optionally substituted with 1 or2 substituents selected from halo, hydroxyl, and C₁-C₆ alkyl; m is zero;and R¹⁹, R²⁰ and R²¹ are C₁-C₄ alkyl.
 41. The method of claim 40,wherein: R¹³, R¹⁹, R²⁰ and R²¹ are methyl; and R⁵ is phenyl.
 42. Themethod of claim 29, wherein the catalyst is in the form of an acidaddition salt composed of compound (VIIA) or (VIIB) and a Brønsted acid.43. A reaction system comprising a nonmetallic chiral catalystcontaining a Group 15 or Group 16 heteroatom, and an enolizable aldehydehaving the structure of formula (I) and, optionally, an additionalaldehyde has the structure of formula (II)

in which: R¹ and R² are independently selected from hydrocarbyl,substituted hydrocarbyl, heteroatom-containing hydrocarbyl, andsubstituted heteroatom-containing hydrocarbyl.
 44. The reaction systemof claim 43, wherein the additional aldehyde is present.
 45. Thereaction system of claim 44, wherein R¹ and R² are independentlyselected from C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄heteroalkyl, substituted C₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substitutedC₅-C₂₄ aryl, C₁-C₂₄ heteroaryl, substituted C₁-C₂₄ heteroaryl, C₆-C₂₄aralkyl, substituted C₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, andsubstituted C₂-C₂₄ heteroaralkyl.
 46. The reaction system of claim 45,wherein R¹ and R² are independently selected from C₁-C₁₂ alkyl,substituted C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, substituted C₁-C₁₂heteroalkyl, C₅-C₁₄ aryl, substituted C₅-C₁₄ aryl, C₃-C₁₄ heteroaryl,substituted C₃-C₁₄ heteroaryl, C₆-C₁₆ aralkyl, substituted C₆-C₁₆aralkyl, C₃-C₁₆ heteroaralkyl, and substituted C₃-C₁₆ heteroaralkyl. 47.The reaction system of claim 43, wherein the additional aldehyde isabsent.
 48. The reaction system of claim 47, wherein R¹ is selected fromhydrogen, C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl,substituted C₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl,C₁-C₂₄ heteroaryl, substituted C₁-C₂₄ heteroaryl, C₆-C₂₄ aralkyl. 49.The reaction system of claim 48, wherein R¹ is selected from hydrogen,C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₁-C₁₂ heteroalkyl, substitutedC₁-C₁₂ heteroalkyl, C₅-C₁₄ aryl, substituted C₅-C₁₄ aryl, C₃-C₁₄heteroaryl, substituted C₃-C₁₄ heteroaryl, C₆-C₁₆ aralkyl, substitutedC₆-C₁₆ aralkyl, C₃-C₁₆ heteroaralkyl, and substituted C₃-C₁₆heteroaralkyl.
 50. The reaction system of claim 43, wherein the catalystis effective to raise the energy level of the highest occupied molecularorbital (HOMO) of the enolizable aldehyde
 51. The reaction system ofclaim 43, wherein the heteroatom of the catalyst is selected from thegroup consisting of nitrogen, oxygen, sulfur and phosphorus.
 52. Thereaction system of claim 51, wherein the heteroatom is nitrogen.
 53. Thereaction system of claim 52, wherein the catalyst is a secondary amineor an acid addition salt thereof.
 54. The reaction system of claim 53,wherein the secondary amine is chiral with respect to an axis, plane orcenter of asymmetry.
 55. The reaction system of claim 11, wherein thesecondary amine has the structure of (III)

wherein R³ and R⁴ are independently selected from the group consistingof hydrocarbyl, substituted hydrocarbyl, heteroatom-containinghydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or aretaken together to form a ring, such that the amine is a cyclic secondaryamine.
 56. The reaction system of claim 55, wherein R³ and R⁴ are takentogether to form a 3- to 15-membered, optionally substituted ring. 57.The reaction system of claim 56, wherein the secondary amine has thestructure of formula (IV)

wherein n is zero or 1, X is a moiety that contains up to 50 atoms andis selected from the group consisting of hydrocarbylene, substitutedhydrocarbylene, heteroatom-containing hydrocarbylene and substitutedheteroatom-containing hydrocarbylene, and X¹ and X² are independentlysubstituted or unsubstituted methylene.
 58. The reaction system of claim57, wherein the secondary amine has the structure of formula (V)

in which: R⁵, R⁶, R⁷, and R⁸ are independently selected from hydrogen,hydroxyl, sulfhydryl, carboxyl, amino, mono-(C₁-C₂₄ alkyl)-substitutedamino, di-(C₁-C₂₄ alkyl)-substituted amino, mono-(C₅-C₂₄aryl)-substituted amino, di-(C₅-C₂₄ aryl)-substituted amino,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino, C₆-C₂₄arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or wherein R⁵ and R⁶, and/or R⁷ and R⁸, together form acarbonyl group ═O.
 59. The reaction system of claim 58, wherein X is—(CR⁹R¹⁰)—(X³)_(q)—(CR¹¹R¹²)_(t) and the secondary amine therefore hasthe structure of formula (VI)

in which X³ is O, S, NH, NR¹³, or CR¹⁴R¹⁵, q is zero or 1, t is zero or1, and R⁹, R¹⁰, R¹¹, R¹², R¹⁴, and R¹⁵ are independently selected fromhydrogen, hydroxyl, sulfhydryl, carboxyl, amino, mono-(C₁-C₂₄alkyl)-substituted amino, di-(C₁-C₂₄ alkyl)-substituted amino,mono-(C₅-C₂₄ aryl)-substituted amino, di-(C₅-C₂₄ aryl)-substitutedamino, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted amino, C₂-C₂₄alkylamido, C₆-C₂₄ arylamido, imino, C₂-C₂₄ alkylimino, C₆-C₂₄arylimino, nitro, nitroso, C₁-C₂₄ alkoxy, C₅-C₂₄ aryloxy, C₆-C₂₄aralkyloxy, C₂-C₂₄ alkylcarbonyl, C₆-C₂₄ arylcarbonyl, C₂-C₂₄alkylcarbonyloxy, C₆-C₂₄ arylcarbonyloxy, C₂-C₂₀ alkoxycarbonyl, C₆-C₂₄aryloxycarbonyl, halocarbonyl, carbamoyl, mono-(C₁-C₂₄alkyl)-substituted carbamoyl, di-(C₁-C₂₄ alkyl)-substituted carbamoyl,di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄ aryl)-substituted carbamoyl, mono-(C₅-C₂₄aryl)-substituted carbamoyl, di-(C₅-C₂₄ aryl)-substituted carbamoyl,thiocarbamoyl, mono-(C₁-C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁-C₂₄alkyl)-substituted thiocarbamoyl, di-N-(C₁-C₂₄ alkyl)-N-(C₅-C₂₄aryl)-substituted thiocarbamoyl, mono-(C₅-C₂₄ aryl)-substitutedthiocarbamoyl, di-(C₅-C₂₄ aryl)-substituted thiocarbamoyl, carbamido,formyl, thioformyl, sulfo, sulfonato, C₁-C₂₄ alkylthio, C₅-C₂₄ arylthio,C₁-C₂₄ alkyl, substituted C₁-C₂₄ alkyl, C₁-C₂₄ heteroalkyl, substitutedC₁-C₂₄ heteroalkyl, C₅-C₂₄ aryl, substituted C₅-C₂₄ aryl, C₁-C₂₄heteroaryl, substituted C₁-C₂₄ heteroaryl, C₂-C₂₄ aralkyl, substitutedC₆-C₂₄ aralkyl, C₂-C₂₄ heteroaralkyl, and substituted C₂-C₂₄heteroaralkyl, or wherein R⁹ and R¹⁰, and/or R¹¹ and R¹², together forman oxo moiety ═O; and R¹³ is selected from C₁-C₁₂ hydrocarbyl,substituted C₁-C₁₂ hydrocarbyl, heteroatom-containing C₁-C₁₂hydrocarbyl, and substituted heteroatom-containing C₁-C₁₂ hydrocarbyl.60. The reaction system of claim 59, wherein q is zero, and at least oneof R⁵ through R⁸ is carboxyl.
 61. The reaction system of claim 60,wherein the secondary amine is L-proline.
 62. The reaction system ofclaim 61, wherein q is 1, X³ is NR¹³, t is zero, R⁵ and R⁷ are hydrogen,and R⁶ is —CR¹⁶R¹⁷R¹⁸, such that the secondary amine has the structureof formula (VIIA) or (VIIB)

wherein: R⁸ and R¹³ are as defined previously; and R¹⁶ and R¹⁷ areindependently selected from hydrogen, halo, hydroxyl, C₁-C₁₂hydrocarbyl, substituted C₁-C₁₂ hydrocarbyl, heteroatom-containingC₁-C₁₂ hydrocarbyl, and substituted heteroatom-containing C₁-C₁₂hydrocarbyl; and R¹⁸ is a cyclic group optionally substituted with 1 to4 non-hydrogen substituents and containing zero to 3 heteroatoms. 63.The reaction system of claim 62, wherein: R⁸ has the structure—(L)_(m)—CR¹⁹R²⁰R²¹ wherein m is zero or 1, L is C₁-C₆ alkylene, andR¹⁹, R²⁰ and R²¹ are C₁-C₁₂ hydrocarbyl; R¹³ is C₁-C₁₂ hydrocarbyl; R ⁶and R¹⁷ are independently selected from hydrogen and C₁-C₁₂ hydrocarbyl;and R¹⁸ is a monocyclic aryl or heteroaryl group optionally substitutedwith 1 to 4 substituents selected from halo, hydroxyl, and C₁-C₁₂hydrocarbyl.
 64. The reaction system of claim 63, wherein: R¹³ is C₁-C₆alkyl; R¹⁶ and R¹⁷ are hydrogen; R¹⁸ is phenyl optionally substitutedwith 1 or 2 substituents selected from halo, hydroxyl, and C₁-C₆ alkyl;m is zero; and R¹⁹, R²⁰ and R²¹ are C₁-C₄ alkyl.
 65. The reaction systemof claim 64, wherein: R¹³, R¹⁹, R²⁰ and R²¹ are methyl; and R⁵ isphenyl.
 66. The reaction system of claim 65, wherein the catalyst is inthe form of an acid addition salt composed of compound (VIIA) or (VIIB)and a Brønsted acid.
 67. A method for synthesizing a sugar molecule,comprising contacting at least one enolizable aldehyde α-substitutedwith a protected hydroxyl group with a catalytically effective amount ofa nonmetallic chiral catalyst containing a Group 15 or Group 16heteroatom under conditions effective to allow the at least oneenolizable aldehyde to undergo an enantioselective aldol couplingreaction.
 68. The method of claim 67, wherein the at least oneenolizable aldehyde comprises two enolizable aldehydes eachα-substituted with a protected hydroxyl group.
 69. The method of claim68, wherein the protected hydroxyl group of the first enolizablealdehyde is of the formula —O—Pr¹ and the protected hydroxyl group ofthe second enolizable aldehyde is of the formula —O—Pr², wherein Pr¹ andPr² are different.
 70. The method of claim 69, wherein Pr¹ and Pr² areorthogonally removable.
 71. The method of claim 67, wherein the aldolcoupling reaction results in trimerization of the at least oneenolizable aldehyde to give a protected dihydroxy tetrahydropyran. 72.The method of claim 67, wherein the aldol coupling reaction results indimerization of the at least one enolizable aldehyde, and the methodfurther includes an additional coupling reaction effective to give aprotected dihydroxy tetrahydropyran.